The pyrimidine compound with which the present invention is concerned has the following structural formula ##STR1## and is known as gepirone. The hydrochloride salt has been referred to in the prior art as MJ 13805-1 and as gepirone hydrochloride. Other acid addition salts thereof are named by combining "gepirone" with the appropriate word to define the acid from which it is prepared as in "gepirone hydrochloride". The latter is the U.S. adopted name (USAN); refer to the "1986 USAN and the USP Dictionary of Drug Names" which is published by the United States Pharmacopeial Convention, Inc.
The synthesis of the compound and the disclosure of its anxiolytic properties are described in the following patents and publications.
1. D. L. Temple, Jr., U.S. Pat. No. 4,423,049, issued Dec. 27, 1983.
2. Annual Reports in Medicinal Chemistry: Volume 21, Editor-in-Chief D. M. Bailey, Academic Press, Inc., 1986, Pages 15, 43.
Gepirone has also been disclosed as an anxiolytic agent with antidepressant properties.
3. Eison, et al., IUPHAR. Abstr. (London):2018 (1984).
4. Eison, et al., Neurosci. Abstr. 10:259 (1984).
5. Eison, et al., Eur. J. Pharmacol., 111:389-392 (1985).
6. Eison, et al. Drugs of the Future, 10:456-457 (1985).
7. Eison, et al., Neurosci. Abstr. 11:186 (1985).
8. Gehlbach, et al., Neurosci. Abstr. 11:186 (1985).
References 3-8 speculate that gepirone's behavioral and neurochemical effects in pre-clinical testing suggest potential use as a mixed anxiolytic-antidepressant agent. Reports of anxiolytic agents demonstrating some antidepressant properties are known, e.g. alprazola, a benzodiazepine anxiolytic agent with some antidepressant properties. This type of psychotropic profile has been considered to be of value since anxious patients often present with some symptoms of accompanying depression.
It is to be appreciated however that there are different types of depression, ranging from the natural depressed mood, which is universally experienced, to major depressive illness which is a condition of high morbidity and a substantial mortality. The increasing severity of the differing types of depression, going from minor, or secondary, forms with only some depressive symptoms to a full-blown major, or primary, depressive disorder is directly proportional to the increasing suffering and misery experienced by the patients and their families. Treatment of depression is complicated unfortunately as depressive illness is not a single entity but a heterogenous group of disorders, comprised of several subtypes. It is important to realize that these subtypes involve different patient populations and respond differently to antidepressant treatments. This is evidenced by the observation that about one-third of the patients in a typical treatment population are non-responders or respond only partially. Efforts have continued for years to improve differential diagnosis of the various depressive illness subtypes so that the most appropriate treatment for that subtype may be employed. This is particularly important in selecting antidepressant drug therapy since the various depressive illness subtypes demonstrate different responses to antidepressant agents.
Adding further confusion to the selection of appropriate antidepressant treatment is the lack of standardized diagnostic terminology. For example, the more severe major depressive disorder subtype, melancholia (DSM-III), has been variously classified as: "major affective disorder", "endogenous depression", "typical depression", "melancholic depression", "major depressive disorder", "primary depressive disorder" and "depressed phase of affective psychoses". This subtype of depressive illness is characterized by severe depression, retardation or agitation, guilt, insomnia, diurnal varation of mood (worse in morning), loss of appetite, and positive response to electric convulsion therapy and the tricyclic-class of antidepressant drugs.
A different severe primary depressive disorder subtype is classified as "atypical depression". The depressed patients comprising this subtype of depressive illness may be characterized by anxiety, phobic and histrionic symptoms, extreme sensitivity to rejection, emotional overreactivity, being energetic and highly active when not depressed, but suffering fatigue, initial insomnia and reversed diurnal variation (mood worse at night) when depressed. This class of patient may sometimes score low on "depression" psychometric instruments, since its members do not display guilt, delusional ideas, severe weight loss, or suicidal intent and are not usually hospitalized for treatment. Because these patients respond poorly to electic convulsion therapy and standard antidepressant drug treatment, they present real difficulties and suffer much distress. The current treatment of choice employed for "atypical" depressives is administration of monoamine oxidase inhibitors (MAOI's), an older class of drugs that have more restricted usage due their inherent side-effects, not the least of which is the considerable risk due to food and drug incompatabilities with MAOI administration. All exposure to indirect acting sympathomimetic amines, particularly tyramine (found in red wine, aged cheeses, aged proteins, etc.) must be avoided in MAOI-treated patients. Many common over-the-counter medicines must also be avoided including almost all cold medicines (nasal sprays as well), diet pills, antihistamines, some suppositories and so forth.
These two different primary depressive disorders, involving severe illness as briefly described above may be contrasted with minor, or secondary, depressive disorders such as anxiety with depressed mood or minor depression with anxiety. These secondary disorders are comprised of patients with much less severe depressive illness than those suffering from a primary depressive disorder. Also distinguishing these groups of patients is that different treatments are employed for each. Treatments common to the primary depressive disorders such as tricyclic antidepressant agents, MAO inhibitors and electric convulsive shock are not used to treat patients suffering from neurotic disorders with secondary depressive symptoms. These patients are usually treated by such treatment modalities as psychotherapy and/or antianxiety drug therapy. Similarly, treatment appropriate for mixed anxiety-depressive illness is not usually effective in relieving core symptoms of primary depressive disorders. While these observations may be used as an empirical guide in selecting an appropriate drug treatment, there is of course no way to predict success of drug therapy beforehand in each of these subtypes.
The most pertinent consideration of prior art concerns buspirone, a novel anxiolytic agent with structural and pharmacological similarities to gepirone. While buspirone demonstrates potent anxiolytic activity with antidepressant properties, it was not found to be particularly effective against primary depression, particularly in patients with melancholia where the drug had no effect. (cf: Schweizer, et al., Psychopharmacol. Bull., 22: 183-185 (1986).
The unexpected finding comprising the present invention is that gepirone is effective in treating severely affected patients suffering from primary depressive disorders such as endogenous depression with melancholia and atypical depression. There was nothing in the prior art which disclosed or suggested beforehand that gepirone could be utilized in treating the more severe primary depressive illnesses. The pharmacologic profile of gepirone as an anxiolytic agent with antidepressant properties indicated that gepirone could have usefulness in treating the minor, or secondary depression-anxiety subtype of patient. Drugs useful in treating secondary depression subtypes are not usually employed in treating primary depressive illnesses. In spite of continuing antidepressant drug development activity of the past twenty years, no anxiolytic agent with antidepressant properties has been approved by the FDA for effective treatment of severe primary depressive illnesses.
In summary, gepirone and its pharmacologically acceptable salts bear no structural resemblance to any therapeutic agent accepted as being useful in the treatment of certain primary depressive disorders, particularly for more severely affected patients. It is now appreciated by those skilled in the art that depressive illness is comprised of distinguishable disease states with differently defined patient populations and drug responses. It is further appreciated that agents which are effective in treating one subtype of depression may be ineffective against other of the subtypes; i.e. it is not obvious beforehand if an agent will effectively alleviate a primary depressive disorder of any one clinical subtype. There exists nothing in the prior art which teaches or suggests that the instant compounds, gepirone and its salts, would be useful in alleviation of major depression with melancholia or atypical depression.